Process for the production of citalopram

ABSTRACT

The invention relates to a process for the manufacture of salts of citalopram in high purity. By the careful selection of solvents and the careful manipulation of the pH value, citalopram salts may be isolated in the absence of 5-chlorocitalopram, 5-bromocitalo-pram, desmethyl-citalopram and 5-carobxyamide citalopram.

[0001] This invention relates to citalopram, in particular salts ofcitalopram and a process for the manufacture of said salts in very highpurity.

[0002] Citalopram is a well-known anti-depressant drug which has been onthe market for a number of years. It has the structure shown below.

[0003] Citalopram is a selective, centrally acting serotonin(5-hydroxytryptamine:5-HT) re-uptake inhibitor and accordingly possessesanti-depressant activity. The anti-depressant activity of the compoundhas been reported in a number of publications and citalopram has furtherbeen disclosed as showing potential in the treatment of dementia andcerebrovascular disorders.

[0004] Citalopram was first disclosed in U.S. Pat. No. 4,136,193 whichdescribes a number of processes for its preparation. Once manufactured,the citalopram base is generally converted to a salt using conventionalprocedures although it can be used as a free base. Hydrobromide saltsare especially preferred since they are orally available.

[0005] Since the publication of the above mentioned U.S. patent, anumber of further processes for the preparation of citalopram have beendevised and in many of these, as well as in the above U.S. patent, thelast step of the process involves the conversion of a group differentfrom the cyano in the 5 position of the phthalane ring into the 5-cyanogroup. Preferably the conversion takes place from a bromine analogue.

[0006] As is well-known however, impurities are inevitably formed duringthe cyanation reaction and these impurities are difficult to separatefrom the desired end product. Impurities also remain from earlysynthesis stages and accordingly, extensive purification procedures arerequired.

[0007] Where the final stage of citalopram manufacture involvescyanation of 5-bromine analogue to the corresponding nitrile, the mainimpurities encountered are:

[0008] Various purification procedures are already known in the art forpurifying a crude citalopram mixture produced after such a cyanationreaction. For example, GB 2356199 teaches that the impurities may beremoved using a conventional film distillation technique. The crude baseis simply distilled using, for example, a thin film distillationapparatus yielding a purer citalopram material. The base product maythen be formed into the salt. GB 2357762 describes an alternativeprocedure in which the crude free base is simply crystallised prior toconversion to the salt.

[0009] There still remains the need however, to devise efficient andmore economic purifycation procedures especially for use on industrialscale where, for example, the use of film distillation apparatus may beprohibitively expensive.

[0010] The present inventors have now found an alternative and rapid wayof isolating purer citalopram salts substantially in the absence of theabove-mentioned impurities without using potentially time consumingcrystallisation techniques or expensive film distillation apparatus.Rather, the present inventors have found that by the careful selectionof solvents and the careful manipulation of pH, citalopram salts may beisolated in very high purity in the absence of the major impurities5-chlorocitalopram, 5-bromocitalopram, desmethyl-citalopram and5-carboxyamide citaloprarn.

[0011] Thus, viewed from one aspect the invention provides a process forthe preparation of a salt of citalopram comprising:

[0012] (A) dissolving citalopram in a solvent selected from acetone,alcohol, or toluene or mixtures thereof and adding oxalic acid;

[0013] (B3) separating the precipitated citalopram oxalate, e.g. byfiltration;

[0014] (C) suspending said citalopram oxalate in water and adding a basein an amount sufficient to liberate citalopram, e.g. to a pH 9 to 10;

[0015] (D) extracting the liberated citalopram with an organic solvent,isolating the organic phase and evaporating said solvent;

[0016] optionally repeating steps (A) to (D),

[0017] repeating steps (A) and (B) and subsequently;

[0018] (E) suspending said citalopram oxalate in water and adding baseto a pH 6 to 7;

[0019] (F) adding a solvent selected from toluene, cyclohexane,n-hexane, n-heptane, isopropyl ether or xylene or mixtures thereof andisolating the aqueous phase;

[0020] (G) adding base to said aqueous phase in an amount sufficient toliberate citalopram and extracting the liberated citalopram with anorganic solvent, isolating the organic phase and evaporating saidsolvent;

[0021] (H) dissolving said citalopram in an alcohol solvent, adding anacid and separating the precipitated citalopram salt.

[0022] Viewed from another aspect the invention comprises a process forthe separation of desmethyl citalopram from a crude mixture thereof withcitalopram base comprising:

[0023] (A) dissolving citalopram in a solvent selected from acetone,alcohol, or toluene or mixtures thereof and adding oxalic acid;

[0024] (B) separating the precipitated citalopram oxalate;

[0025] (C) suspending said citalopram oxalate in water and adding a basein an amount sufficient to liberate citalopram, e.g. to a pH 9 to 10;

[0026] (D) extracting the liberated citalopram with an organic solvent,isolating the organic phase and evaporating said solvent;

[0027] optionally repeating steps (A) to (D).

[0028] Viewed from a still further aspect the invention provides aprocess for the separation of 5-chlorocitalopram and 5-bromocitalopramfrom a crude mixture of citalopram oxalate comprising:

[0029] (E) suspending citalopram oxalate in water and adding base to apH 6 to 7;

[0030] (F) adding a solvent selected from toluene, cyclohexane,n-hexane, n-heptane, isopropyl ether or xylene or mixtures thereof andisolating the aqueous phase.

[0031] Viewed from another aspect the invention provides a process forthe separation of 5-carboxyamide from a crude mixture of citalopramcomprising:

[0032] (H) dissolving citalopram in an alcohol solvent, adding an acidand separating the precipitated salt, e.g. by filtration.

[0033] Viewed from a still yet further aspect the invention providescitalopram or salts thereof obtained by the processes of the inventionas well as their use in medicine and pharmaceutical salts comprising thesame.

[0034] As used herein “citalopram” refers to the free base thereof.

[0035] In part (A) of the process of the invention, the crude citaloprambase should preferably be dissolved in acetone. Without wishing to belimited by theory, it is believed that desmethyl citalopram is removedin the solvent washings in step (13) when the citalopram oxalate salt isisolated. It has been found that the most efficient elimination ofdesmethyl citalopram occurs when the solvent employed is acetone.

[0036] Isolation of the precipitated citalopram oxalate in step (B) maybe achieved by, for example, filtration or centrifugation or by anyother conventional technique for separating a solid from a liquid. Thecitalopram oxalate is precipitated (it being insoluble in the organicsolvent employed) and isolation should not be effected by evaporatingoff the organic phase since the desmethyl citalopram would, of course,not be removed in such a procedure.

[0037] The base used to liberate citalopram from its oxalate in step (C)may be any conventional base which is compatible with citalopram.Suitable bases include NaOH, KOH and various organic bases however, itis preferred if ammonia is used as the base. The pH of the solution instep (C) needs to be increased to a value sufficient to ensurecitalopram base is liberated and the required pH will be readilydetermined by the sildled chemist. It is preferred however if the pH isadjusted to between 8.5 to 10, especially, 9.0 to 9.5, most preferably9.0 to 9.2. The pH can of course be monitored using standard indicatorsor other pH measuring apparatus.

[0038] The liberated citalopram free base may be extracted from theaqueous solution by using a standard organic solvent (Step D). Mostsuitable in this regard is toluene although other hydrocarbon solventssuch as xylene, hexane, heptane etc. could be employed equallysuccessfully. The organic phase formed should be separated by a simplelayer separation procedure and the solvent may then be evaporated off bysimple distillation or under reduced pressure. Conveniently however, thesolvent is removed under atmospheric pressure conditions so as tomaintain the liberated citalopram as an oil. By using atmosphericpressure evaporation, it is likely that some traces of solvent willremain (perhaps up to 10%) hence maintaining the liberated citalopram inan oil form.

[0039] In order to remove any remaining traces of desmethyl citalopramit may be necessary to repeat the oxalate formation and subsequent baseliberation steps (A to D).

[0040] Without wishing to be limited by theory, it is believed that thefurther main impurities, bromo/chloro citalopram can be removed bycareful manipulation of pH and then by washing in particular solvents.

[0041] In order to remove these impurities according to the invention,it is necessary to add citalopram oxalate to water and adjust the pH ofthe solution to 6 to 7, preferably 6.2 to 7 (Step E). Again the base maybe any base suitable for this task, e.g. as described above in relationto step (C), however, ammonia is again preferred.

[0042] The inventors have surprisingly found that at this pH citalopramoxalate remains substantially in its salt form but the salts of thechloro and bromo intermediates tend to convert back to theircorresponding bases. On organic washing therefore (Step F), it hassurprisingly proved possible to remove the impurities in the organicwashings whilst maintaining the desired product in the aqueous phase.The organic washing solvent is conveniently toluene, cyclohexane,n-hexane, n-heptane, isopropyl ether or xylene or mixtures thereof. In apreferred embodiment the solvent is toluene, cyclohexane or a mixturethereof.

[0043] After the impurities have been removed in the organic phase, theaqueous layer can then be fully basified and the citalopram free baseextracted into an organic solvent for subsequent conversion to thedesired citalopram salt (Step G). Again, the solvent used to extract theliberated citalopram can be any solvent suitable for the task, e.g.those described above with respect to step (D).

[0044] Most suitable in this regard is again toluene although otherhydrocarbon solvents such as xylene, hexane, heptane etc could beemployed equally successfully. The solvent may then be evaporated off bysimple distillation or under reduced pressure. Conveniently however, thesolvent is removed under atmospheric pressure conditions so as tomaintain the liberated citalopram as an oil. By using atmosphericpressure evaporation, it is likely that some traces of solvent willremain (perhaps up to 10%) hence maintaining the liberated citalopram inan oil form.

[0045] It is during the final stage, i.e. conversion to the desiredsalt, that the inventors believe that the 5-carboxyamide citalopramimpurity may be removed.

[0046] This is achieved by dissolving the citalopram in an alcoholsolvent, especially isopropyl alcohol or methanol. The aqueous saltforming agent, i.e. acid, is then added to form the citalopram salt(Step H). The citalopram salt crystals may be isolated conventionally byfiltration or centrifugation but the 5-carboxyamide citalopram impurityremains in the organic phase and is hence easily and surprisinglyremoved with the organic phase.

[0047] The salt to be manufactured is preferably the hydrobromide,hydrochloride or oxalate salt.

[0048] The purification technique of the present invention isparticularly suitable for preparing citalopram hydrobromide where theinitial citalopram mixture has been prepared via a cyanation of5-bromocitalopram. However, the process is equally suitable for thepurification of the crude citalopram made by any other process. Othersuch processes are described in, for example, EP-A-171943.

[0049] The cyanation of bromocitalopram is easily carried out using, forexample, sodium cyanide or preferably copper cyanide. Bromocitalopramitself can be manufactured in a number of ways, for example, asdescribed in U.S. Pat. No. 4,136,193.

[0050] Depending on the nature of the impurities present it may bepossible to omit some of the purification stages of the process of theinvention. Thus, if no desmethyl citalopram is present in a crudecitalopram mixture, it may be possible to omit stages (A) to (D) andsimply remove the other impurities following the teaching of steps (E)to ([). This forms a further aspect of the invention. Similarly, if a5-carboxyamide citalopram impurity is not present then conversion to thedesired salt may be effected without following the explicit teachings ofstep (H). Hence the present invention also provides a process asdescribed in steps (A) to (G) and steps (A) to (D) followed by step (H).

[0051] Citalopram salts made by the process of the invention may beformulated into pharmaceutical compositions as is well known in the art.Such compositions may take the form of tablets which may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tabletingmachine. Examples of adjuvants or diluents comprise: corn starch, potatostarch, talcum, magnesium stearate, gelatin, lactose, gums and is thelike. Any other adjuvant or additive colourings, aroma, preservatives,taste masking agents etc. may be used provided that they are compatiblewith the active ingredient.

[0052] The active ingredient may also be formulated as a solution forinjection which may be prepared by solving the active ingredient andpossible additives in a part of the solvent for injection, preferablysterile water, adjusting the solution to the desired volume,sterilisation of the solution and filling in suitable ampoules or vials.Again, any suitable additive conventionally used in the art may be addedsuch as tonicity agents, preservatives, antioxidants, etc.

[0053] The amount of citalopram administered to a patient is dependenton the nature of the patient and will be readily determined by theskilled physician. Tablets may however comprise, for example, 20 mg or40 mg doses.

[0054] Citalopram may be administered along with any otherpharmaceutical with which it is compatible and additional activeingredients can of course be formulated into compositions withcitalopram as is well known in the art.

[0055] The invention will now be further described with reference to thefollowing non-limiting examples.

EXAMPLE 1 1-(3-Dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3dihydrobenzofuran-5-carbonitrile oxalate (Citalopram Oxalate).

[0056] Citalopram was prepared substantially as described in Example 2of U.S. Pat. No. 4,136,193 although toluene was used instead of benzene.100 g of citalopram (0.30 mol) with a desmethyl citalopram content of upto 5.0% was added to acetone (300 ml) and the resulting solution stirredfor 15 min. at 40° C. To the above clear solution was added oxalic acid(40 g, 0.31 mol), dissolved in acetone (300 ml) and the resultingmixture heated to 50-55° C. The mixture was cooled and the whitecrystals of the title compound were filtered off at room temperature anddried at 60° C. for 6 hrs at atmospheric pressure.

[0057] Citalopram oxalate prepared as in Example 1 (105 g, 0.25 mol) wassuspended in water (525 ml) and the pH was adjusted to 9.0-9.2 by theaddition of ammonia. The mixture was stirred for 30 minutes andextracted with toluene twice (250 ml). The organic phases were separatedand washed with water (100 ml). Toluene layer was concentrated undervacuum. Acetone (300 ml) is added to the residue and the mixture stirredfor 15 min. at 40° C. To the above clear solution was added oxalic acid(33 g, 0.26 mol), dissolved in Acetone (300 ml) and the mixture washeated to 50-55° C. The white crystals of the title compound werefiltered off at room temperature and dried at 60° C. for 6 hrs atatmospheric pressure.

[0058] Yield: 90 g (85%). Desmethyl citalopram content less than 0.1%.

EXAMPLE 2 1-(3-Dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3dihydrobenzofuran-5-carbonitrile hydrobromide (Citalopramhydrobromide).

[0059]1-(3-Dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3-dihydrobenzofuran-5-carbonitrileoxalate (90 g, 0.21 mol) prepared as per example 1 was suspended inwater (500 ml) and aqueous ammonia (20-25%) was added to adjust the pHof the solution to 6.2-7.0 (approximately 20 ml). The solution isstirred for 15 min. The above solution was washed with toluene (6×50 ml)and the organic phases are separated. To the remaining aqueous phase wasadded ammonia (20-25%) to bring the pH to 9.0-9.2. The mixture wasstirred for 15 min, and extracted with toluene (2×250 ml). The organicphases were washed with NaCl solution (100 ml, 10%) and the tolueneremoved in vacuum to leave an oily residue. To the residue was added 350ml isopropylalcohol and the clear solution filtered through Celite®. Tothe resulting clear solution is added 35 g of 48% aq. hydrobromic acidand the mixture is stirred for 1 hr at 50° C. After cooling to 20° C.,the crystals are filtered and dried.

[0060] Yield: 75 g (85%) Purity: 99.7%

1. A process for the preparation of a salt of citalopram comprising: (A)dissolving citalopram in a solvent selected from acetone, alcohol, ortoluene or mixtures thereof and adding oxalic acid; (B) separating theprecipitated citalopram oxalate, e.g. by filtration; (C) suspending saidcitalopram oxalate in water and adding a base in an amount sufficient toliberate citalopram; (D) extracting the liberated citalopram with anorganic solvent, isolating the organic phase and evaporating saidsolvent; optionally repeating steps (A) to (D), repeating steps (A) and(B) and subsequently; (E) suspending said citalopram oxalate in waterand adding base to a pH 6 to 7; (F) adding a solvent selected fromtoluene, cyclohexane, n-hexane, n-heptane, isopropyl ether or xylene ormixtures thereof and isolating the aqueous phase; (G) adding base tosaid aqueous phase in an amount sufficient to liberate citalopram andextracting the liberated citalopram with an organic solvent, isolatingthe organic phase and evaporating said solvent; (H) dissolving saidcitalopram in an alcohol solvent, adding an acid and separating theprecipitated citalopram salt.
 2. A process for the separation ofdesmethyl citalopram from a crude mixture thereof with citalopram basecomprising: (A) dissolving citalopram in a solvent selected fromacetone, alcohol, or toluene or mixtures thereof and adding oxalic acid;(B) separating the precipitated citalopram oxalate; (C) suspending saidcitalopram oxalate in water and adding a base in an amount sufficient toliberate citalopram; (D) extracting the liberated citalopram with anorganic solvent, isolating the organic phase and evaporating saidsolvent; optionally repeating steps (A) to (D).
 3. A process for theseparation of 5-chlorocitalopram and 5-bromocitalopram from a crudemixture of citalopram oxalate comprising: (E) suspending citalopramoxalate in water and adding base to a pH 6 to 7; (F) adding a solventselected from toluene, cyclohexane, n-hexane, n-heptane, isopropyl etheror xylene or mixtures thereof and isolating the aqueous phase.
 4. Aprocess for the separation of 5-carboxyamide from a crude mixture ofcitalopram comprising: (H) dissolving citalopram in an alcohol solvent,adding an acid and separating the precipitated salt.
 5. Citalopram orsalts thereof obtained by the process of claim
 1. 6. A pharmaceuticalcomposition comprising citalopram or a salt thereof as claimed in claim5.
 7. Citalopram or salts thereof obtained by the process of claim
 2. 8.A pharmaceutical composition comprising citalopram or a salt thereof asclaimed in claim
 7. 9. Citalopram or salts thereof obtained by theprocess of claim
 3. 10. A pharmaceutical composition comprisingcitalopram or a salt thereof as claimed in claim
 9. 11. Citalopram orsalts thereof obtained by the process of claim
 4. 12. A pharmaceuticalcomposition comprising citalopram or a salt thereof as claimed in claim11.